The earliest developmental events occur while the zygotic genome is inactivated; thus, vertebrate development depends on maternally supplied gene products. Mutations that disrupt the genes that encode these necessary maternal factors, maternal-effect genes, can be teratogenic or lethal. Females with dysfunctional maternal-effect genes are grossly normal, due to normal gene function supplied by their mother. However, the progeny of these females develop abnormally regardless of their genotype. Despite increasing awareness of the significant impact maternal products have on vertebrate development and health, only a few maternal-effect genes have been experimentally evaluated through genetic or by interference approaches. For those genes that have been examined, it is clear that inadequate maternal contribution results in early embryonic lethality, or in less severe cases, developmental abnormalities. Similar genetic defects in humans are expected to result in failed implantation or miscarriage before a woman knows she is pregnant. Ten to twenty percent of pregnancies that are diagnosed result in miscarriage; however, many pregnancies go undetected. When these are factored in, the actual percentage of pregnancies that end in miscarriage is estimated to be significantly higher affecting 40-50% of all pregnancies, according to The March of Dimes, The American College of Obstetricians and Gynecologists, The Mayo clinic, and the National Institutes on Child Health and Development. Our long-term research goal is to determine the genetic pathways and cell biological events that direct development of the first axis of the vertebrate embryo. We will continue to use a combination of genetic, molecular genetics, cell biological, and affinity purification approaches in the zebrafish model system. In humans, losses of function mutations in genes whose products are essential for specification of the first embryonic axis will likely cause miscarriage due to severe developmental abnormalities. Moreover, the aspects of oocyte development that we study occur during fetal development in mammals; so, this process is not accessible in humans. In model systems such as zebrafish where fertilization and development of the embryo occur externally every egg produced can be examined for developmental abnormalities. Thus, the zebrafish is a powerful vertebrate system to study maternally controlled processes that are difficult to access in mammals and not possible to study in humans. Significantly, many of the genes known to regulate germline development are conserved from invertebrates to mammals; therefore, an improved understanding of the essential maternal genes that regulate the earliest patterning events of the germline and embryonic development in zebrafish will provide insight into the basis of birth defects, miscarriage, and infertility, and will facilitate comparison with human proteins.